New Mechanism Fundamental to the
Spread of Invasive Yeast Infections Identified

PITTSBURGH—A group of researchers led by Carnegie Mellon University Biological Sciences Professor Aaron Mitchell has identified a novel regulatory gene network that plays an important role in the spread of common, and sometimes deadly, yeast infections. The findings, which establish the role of Zap1 protein in the activation of genes that regulate the synthesis of biofilm matrix, were published in the June 16, 2009, issue of PLoS Biology, a peer-reviewed open-access journal from the Public Library of Science.

Candida albicans is a fungus, more specifically a yeast, which approximately 80 percent of people have in their gastrointestinal and genitourinary tract with no ill effects. However, at elevated levels it can cause non-life threatening conditions like thrush and yeast infections. A C. albicans infection becomes much more serious, and can be lethal, in those with compromised immune systems who have an implantable medical device, such as a pacemaker or artificial joint, or who use broad-spectrum antibiotics. Approximately 60,000 Americans develop such invasive C. albicans infections each year.

Central to such infections is a substance called biofilm matrix. A biofilm is a population of microbes, in this case C. albicans cells, joined together to form a sheet of cells. The cells in the biofilm produce extracellular components such as proteins and sugars, which form a cement-like substance called matrix. This matrix serves to protect the cells of the biofilm, preventing drugs and other stressors from attacking the cells while acting as a glue that holds the cells together. By doing this, the matrix provides an environment in which yeast cells in the biofilm can thrive, promoting infection and drug resistance.

"Biofilms have a major impact on human health and matrix is such a pivotal component of biofilms. It is important to understand how the production of matrix is regulated," Mitchell said.

In the study published in PLoS, Mitchell and colleagues found that the zinc-responsive regulatory protein Zap1 prevents the production of soluble β-1,3 glucan, a sugar that is a major component of matrix. They also identified other genes whose expression is controlled by Zap1, called Zap1 target genes. They found that these genes encode for two types of enzymes, glucoamylases and alcohol dehydrogenases, which both govern the production and maturation of matrix components.

"Understanding this novel regulatory gene network gives us insight into the metabolic processes that contribute to biofilm formation, and the role the network plays in infection," Mitchell said. "By better understanding the mechanisms by which biofilms develop and grow, we can start to look at targets for combating infection."

According to Mitchell, the next steps will be to determine the mechanisms by which Zap1 target genes regulate matrix production. Understanding and targeting these mechanisms will allow the researchers to develop therapeutic small molecules that will block biofilm formation and diagnostic tools that can detect biofilms before infections spread.